A Genetically Vulnerable Myocardium May Predispose to Myocarditis

Campuzano, Òscar; Fernández-Falgueras, Anna; Sarquella-Brugada, Geòrgia; Sanchez, O. Londono; César, Sergi; Mademont, Irene; Allegue, Catarina; Mates, Jesus; Pérez‐Serra, Alexandra; Coll, Mónica; Alcalde, Mireia; Iglesias, Anna; Tirón, Coloma; Gallego, María Ángeles; Ferrer-Costa, Carles; Escribano, C. Segura; Dasí, Concha; Borondo, Juan Carlos; Castellà, J; Arbelo, Elena; Medallo, Jordi; Brugada, Josép; Brugada, Ramón

doi:10.1016/j.jacc.2015.10.049

Cited by 48 publications

(42 citation statements)

References 3 publications

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“…In addition, alterations in SCN5A (encoding the sodium channel), the main gene associated with BrS, have been reported in 1–2% cases of DCM [60], and even AC [61]. In concordance with similar results from recent studies [62], this could suggest that a malignant arrhythmia could appear in early stage before a structural alteration is developed. However, further studies in larger cohorts should be performed to prove or refute this hypothesis.…”

Section: Discussionsupporting

confidence: 80%

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

et al. 2016

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BackgroundSudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases.Methods and FindingsOur cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively.ConclusionsCardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk.

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Section: Discussionsupporting

confidence: 80%

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

et al. 2016

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“…A critical question that arises from this work is whether AVM is merely a second hit revealing inherent myocardial abnormalities of a genetic nature or whether the genetic defects render the myocardium more susceptible to viral infections (36,37), perhaps through infectivity enhanced through a loss of membrane integrity. It has been shown that enteroviral protease 2A cleaves dystrophin, the protein altered in DMD, in a specific fashion, and that rendering dystrophin cleavage resistant through mutagenesis produces AVM resistance (38,39).…”

Section: Discussionmentioning

confidence: 99%

Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

Belkaya

Kontorovich

Byun

et al. 2017

Journal of the American College of Cardiology

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BACKGROUND Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon- (IFN) α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM. OBJECTIVES We evaluated the hypothesis that human genetic factors might underlie AVM in previously healthy children. METHODS We tested the role of TLR3-IFN immunity utilizing human-induced pluripotent stem cell-derived cardiomyocytes. We then performed whole exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral etiologies. RESULTS We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to coxsackievirus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we found that homozygous, but not heterozygous, rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3). CONCLUSIONS Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections.

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“…It remains unclear if myocarditis in AC is a primary phenomenon or reactive to spontaneous cardiomyocyte death. The hypothesis that a genetically vulnerable myocardium may predispose to myocarditis has been advanced and local myocardial production of selected cytokines and alterations in the balance between circulating pro‐inflammatory and anti‐inflammatory cytokines in patients with AC has been demonstrated . In one study, cytokines implicated in granulomatous inflammation promoted rapid intracellular translocation of junctional plakoglobin in cultured neonatal rat ventricular myocytes, suggesting that inflammatory mediators might play a role in AC, even in the absence of infiltrating inflammatory cells .…”

Section: What Is the Role Of Inflammation In The Pathogenesis Of Arrhmentioning

confidence: 99%

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Elliott

Anastasakis

Asimaki

et al. 2019

European J of Heart Fail

109

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It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.

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A Genetically Vulnerable Myocardium May Predispose to Myocarditis

Cited by 48 publications

References 3 publications

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

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